Natural products continue to provide stimulation for the development of creative, interesting, or valuable new chemistry. In this application we propose studies that stem from consideration of the structures or properties of selected natural products that have anticancer properties. In Aim I new methods for the determination of the structure of natural compounds will be developed. The work will primarily address stereochemical issues-specifically, the relative configuration of unknown stereocenters. A major goal will be to develop computational methods that can routinely and reliably be used to deduce stereostructures by guiding proper interpretation of NMR data. In Aim II a new methodology, which has the potential to be broadly applicable in natural product synthesis, will be developed. Namely, relay cross (olefin) metathesis (RelayCM) will be developed. This will allow for efficient (i.e., non-statistical) cross coupling of two different alkenes, even when the two are used in an equimolar ratio. Plans for application of this strategy to accomplish a key convergent cross coupling are presented in the context of a proposed total synthesis of lyngbyaloside B (II). A polyol-acylketene macrolactonization reaction is also showcased in this synthesis. In Aim III the studies related to the biosynthesis of five target compounds will be studied. These are ottelione a (IIIa), salinosporamide A (IIIb), the putative polyenyne biosynthetic precursor to the 9-membered enediyne family (IIIc), uncialamycin (IIId), and okiloactomycin (IIIe). These include compounds with considerable biological relevance to human cancers, including one (IIIb) that is currently in two Phase I clinical trials. Mechanistic considerations, in the light of unprecedented structural features within this group of natural compounds, have led us to propose non-conventional core strategies for the synthesis of each. More specifically, the role of (chemical) spontaneity in biosynthesis drives much of that thinking. In brief, we hypothesize that many natural products undergo their final assembly by non-enzymatic, 'purely chemical' reaction cascades that occur spontaneously under the ambient conditions of the producing organism. Where true, capitalizing on this natural spontaneous event will lead to substantially more efficient chemical synthesis than would otherwise be the case. The driving hypotheses to be tested are: An ambient temperature Cope rearrangement is the key step in the biosynthesis of IIIa. The 2-lactone IIIb is biosynthesized by a spontaneous intramolecular ketene cycloaddition. The polyenyne IIIc is formed by a remarkable and spontaneous cationic cyclization of a highly unsaturated allenyldiynol. The enediyne IIId is formed by spontaneous ring opening of an o-aminoaryloxirane and cyclization of the resultant quinone methide imine. Unique reactivity pairing induces an unusual Diels- Alder reaction leading to IIIe.